Nuclear factor κB (hereinafter referred to as “NF-κB”) associated with signaling from the outside of a cell to the inside of a nucleus is a transcription factor associated with expression of many genes induced in immunological/inflammatory reactions. NF-κB which is a transcription factor generally forms a complex with a control protein called IκB and is localized in cytoplasm as an inactive form. When the IκB of the complex is phosphorylated by an enzyme called IKKβ, degradation of IκB is developed. NF-κB that is released due to the IκB degradation becomes active and translocates from the cytoplasm to the nucleus to activate transcription of a target gene, thereby enhancing production of cytokines such as tumor necrosis factor (hereinafter referred to as “TNF”), interleukin-1 (hereinafter referred to as “IL-1”), and interleukin-6 (hereinafter referred to as “IL-6”) or cell proliferation.
Therefore, it is possible to inhibit activation of NF-κB by way of control of IKKβ, which makes it possible to suppress the production of cytokines such as TNF, IL-1, IL-6 and the like, or the cell proliferation, thereby realizing prevention and/or treatment of diseases considered to be associated with the factors.
Various diseases such as rheumatoid arthritis, asthma, diabetes, and cancer have been known as the diseases considered to be associated with IKKβ (Journal of Molecular Medicine, 82, 434-448 (2004), WO 06/036031).
As compounds having an IKKβ inhibitory activity, condensed furan derivatives disclosed in WO 06/036031, aromatic heterocyclic 5-membered ring carboxamide derivatives disclosed in WO 01/58890, substituted thiophenecarboxamide derivatives disclosed in WO 04/009582, and the like have been known.
Compounds having a urea structure at the 2-position of an indole ring are disclosed in Gazzete Chimica Italiana 48, II, 151-182 (1918), and compounds having an amide structure at the 3-position of an indole ring are disclosed in WO 96/020191. However, these publications do not contain any specific disclosure nor suggestion of compounds having a ureido group at the 2-position and a carbamoyl group at the 3-position of an indole ring, and having a substituted oxy group on benzene ring part of an indole ring. Furthermore it is not mentioned about the IKKβ inhibitory effect of these compounds at all.